Obesity and type 2 diabetes are associated with an increased risk of developing cardiovascular disease, a leading cause of morbidity and mortality in developed countries (Flier (2004) Cell 116, 337-350; Reaven et al., (2004) Recent Prog. Horm. Res. 59, 207-223; Zimmet et al., (2001) Nature 414, 782-787). The predisposition of developing atherosclerosis appears to be the consequence of pathogenic dyslipidemia in insulin-resistant states, which is characterized by hypertriglyceridemia, as well as increased concentrations of low-density lipoprotein (LDL) cholesterol and reduced levels of high-density lipoprotein (HDL) cholesterol (Betteridge (1999) Eur. J. Clin. Invest 29 Suppl. 2, 12-16; Goldberg (2001) J. Clin. Endocrinol. Metab. 86, 965-971). Genetic and epidemiological studies have provided compelling evidence that plasma LDL cholesterol correlates positively with the risk of developing cardiovascular disease (Breslow (2000) Annu. Rev. Genet. 34, 233-254; Sacks and Katan (2002) Am. J. Med. 113 Suppl. 9B, 13S-24S). In addition, increased plasma triglyceride levels have been shown to be an independent risk factor for coronary heart disease. Although genetic factors, environmental influences, and importantly, the interaction of the two all contribute to the progression of cardiovascular disease, it is now understood that dietary intake of saturated and trans fats significantly raises plasma LDL cholesterol while lowering HDL cholesterol (Sacks and Katan (2002) Am. J. Med. 113 Suppl. 9B, 13S-24S; Spady et al. (1993) Annu. Rev. Nutr. 13, 355-381). In fact, dietary intake of saturated and trans fats have a greater hyperlipidemic effect than the intake of cholesterol itself. Despite the strong connection between dietary intake of saturated and trans fats and atherogenic lipid profiles the metabolic pathways and mechanistic basis leading from these lipids to elevated cholesterol levels have been unclear.
The liver plays a central role in the maintenance of systemic lipid homeostasis. Hepatocytes are responsible for the synthesis and secretion of very low-density lipoprotein (VLDL), a precursor for the atherogenic LDL particles. The role of VLDL is to redistribute lipids, primarily triglycerides, for storage and utilization by peripheral tissues. In humans, the liver is also the primary site of de novo lipid synthesis. Hepatic lipogenesis is controlled mainly at the level of gene transcription (Girard et al. (1997) Annu. Rev. Nutr. 17, 325-352; Hellerstein et al. (1996) Annu. Rev. Nutr 16, 523-557). Several transcription factors in the sterol responsive element binding protein (SREBP) family have been shown to be key regulators of the transcriptional activation of lipogenic genes (Horton et al. (2002) J. Clin. Invest. 109, 1125-1131). All SREBP isoforms are synthesized as precursor proteins in the endoplasmic reticulum membrane and undergo two steps of proteolytic cleavage (Brown and Goldstein (1997) Cell 89, 331-340). This leads to release of the N-terminal active forms which subsequently translocate into nucleus and stimulate the expression of target genes. SREBP1a and 1c isoforms (also known as ADD1) are derived from a single gene by alternative usage of transcription start sites, resulting in two proteins with different amino termini (Shimlomura et al. (1997) J. Clin. Invest. 99, 838-845; Tontonoz et al. (1993) Mol. Cell. Bio. 13, 4753-4759); Yokoyama et al. (1993) Cell 75, 187-197), while SREBP2 is encoded by a different gene (Hua et al. (1993) Proc. Natl. Acad. Sci. USA 90, 11603-11607). The activity of SREBPs is regulated by several mechanisms. For example, SREBP 1c mRNA is highly inducible in both fat cells and liver by insulin (Kim et al. (1998) J. Clin. Invest. 101, 1-9; Shimomura et al. (1999) Proc. Natl. Acad. Sci. USA 96, 13656-13661), whereas the proteolytic processing of SREBP2 in cells is stimulated in response to sterol-depletion (Brown and Goldstein (1997) Cell 89, 331-340; Sakai et al. (1996) Cell 85, 1037-1046). Studies in cell culture or mouse liver revealed that SREBP1c and SREBP2 preferentially regulate the expression of genes involved in fatty acid and cholesterol synthesis, respectively (Horton et al. (1998) J. Clin. Invest. 101, 2331-2339; Kim and Spiegelman (1996) Genes Dev. 10, 1096-1107). In contrast, SREBP1a appears to activate both pathways (Horton et al. (2003) Proc. Natl. Acad. Sci. USA 100, 12027-12032; Pai et al. (1998) J. Biol. Chem. 273, 26138-26148). Notably, all three SREBPs induce a severe fatty liver phenotype in transgenic mice with abundant accumulation of triglycerides and cholesterol, suggestive of an imbalance between lipid synthesis and secretion in the transgenic hepatocytes (Horton et al. (1998) J. Clin. Invest. 101, 2331-2339; Shimano et al. (1996) J. Clin. Invest. 98, 1575-1584; Shimano et al. (1997) J. Clin. Invest. 99, 846-854). In addition, hepatic lipogenesis in healthy animals and humans is correlated to lipoprotein secretion causing hepatic steatosis not to develop.
Transcription factors function via docking of coactivator proteins. The coactivators that function with the SREBPs in hepatic lipogenesis have been largely unexplored. Recent studies indicate that the PGC-1 family of coactivators play an important role in liver metabolism (Puigserver and Spiegelman (2003) Endocr. Rev. 24, 78-90).
PGC-1β is a recently identified transcriptional coactivator closely related to PGC-1a whose biological activities have been unknown (Kressler et al. (2002) J. Biol. Chem. 277, 13918-13925; Lin et al. (2002a) J. Biol. Chem. 277, 1645-1648). Although PGC-1β shares a similar tissue distribution with PGC-1β, these two coactivators appear to be differentially regulated during development and in response to changes in nutritional status (Kamei et al. (2003) Proc. Natl. Acad. Sci. USA 100, 12378-12383; Lin et al. (2002a) J. Biol. Chem. 277, 1645-1648; Lin et al. (2003) J. Biol. Chem. 278, 30843-30848). Like PGC-1a, PGC-1β strongly activates mitochondrial biogenesis and cellular respiration in differentiated myotubes and hepatocytes (Lin et al. (2003) J. Biol. Chem. 278, 30843-30848; St-Pierre et al. (2003) J. Biol. Chem. 278, 26597-26603). However, PGC-1β has no apparent effects on the expression of gluconeogenic genes, probably reflecting its lack of ability to coactivate HNF4β and FOXO1, key regulators of hepatic gluconeogenesis.